We have demonstrated that the extent of intracellular polymerization of hemoglobin S is primarily determined by oxygen saturation, hemoglobin concentration and hemoglobin composition. Polymer can be detected in sickle erythrocytes at high oxygen saturation values and accounts for most of the variation among sickle syndromes. Cell heterogeneity can modify polymer formation and an increase in erythrocyte density occurs in sickle cell anemia. Homozygous alpha-thalassemia in sickle cell patients decreases cell heterogeneity and hemolysis, but the small decrease in polymerization is not sufficient to give the dramatic improvement associated with sickle cell disease with HPFH or sickle trait. Our recent direct measurements of cell filterability indicate that the polymer formation at high oxygen saturation does affect cell rheology, particularly in the dense cells. Our calculations of polymer formation can be used to provide goals for major therapeutic approaches, with respect to the amount of polymer reduction necessary to achieve various levels of clinical improvement. The K562 human continuous cell provides a model system for examining the factors which determine the concentration and composition of globin produced within erythroid cells. In order to minimize the heterogeneity of K562 cells in response to hemin induction, K562 cells have been grown in the presence of hemin for long term (22 months). These cells are being characterized and compared with uninduced and short-term induced (4 to 7 days) K562 cells, for intracellular and surface factors which relate to hemoglobin production. The quantitative relationship between hemoglobin S polymerization and pathophysiology remains unclear. We have begun to develop transgenic mice with sickle cell anemia by inserting human sickle beta and alpha genes as a potential animal model for studying the physiological effects associated with hemoglobin S polymerization and abnormal cell rheology.